Spinocerebellar Ataxia 6 (CACNA1A)
| Dred_ID | RD00004 |
| OMIM ID | 183086 |
| Disease name | Spinocerebellar Ataxia 6 |
| Alternative names | SCA6 |
| Category | Genetic diseases, Rare diseases, Neuronal diseases, Skin diseases, Eye diseases, Mental diseases, Ear diseases, Metabolic diseases, Fetal diseases, Liver diseases |
| Phenotype | NIH Rare Diseases: Spinocerebellar ataxia type 6 (SCA6) is a neurological condition characterized by progressive problems with movement. Initial symptoms include problems with coordination and balance (ataxia). Other early signs and symptoms include speech difficulties (dysarthria), involuntary eye movements (nystagmus), and double vision. Over time, individuals with SCA6 may develop loss of coordination in their arms, tremors, and uncontrolled muscle tensing (dystonia). The signs and symptoms of SCA6 typically begin in a person's forties or fifties. Most people with this disorder require wheelchair assistance by the time they are in their sixties. Spinocerebellar ataxia type 6 is caused by mutations in the CACNA1A gene. This condition is inherited in an autosomal dominant pattern.
OMIM: Zhuchenko et al. (1997) reported 8 unrelated families who showed a very similar clinical picture consisting predominantly of mild but slowly progressive cerebellar ataxia of the limbs and gait, dysarthria, nystagmus, and mild vibratory and proprioceptive sensory loss. The disease is insidious and most patients do not realize they are affected initially but do describe a sense of momentary imbalance and 'wooziness' when they make a quick turn or a rapid movement. Typically, it is years after this initial sensation when the patients realize they have developed balance and coordination difficulties. The disease usually progresses over 20 to 30 years, leading to impairment of gait and causing the patient to become wheelchair-bound. In a few older patients, choking has been observed, suggesting involvement of the brainstem. The disease was the cause of death in several members of 2 kindreds. Magnetic resonance imaging (MRI) of the brain in affected individuals demonstrated isolated cerebellar atrophy. |
| Miscellaneouse | OMIM: progressive disorder genetic anticipation age of onset 20-65 years normal alleles have 4 to 18 repeats pathogenic alleles have 19 to 33 repeats |
| Prevalence | Prevalence: 1-9/1000000 (Worldwide),1-9/100000 (Japan); [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | CACNA1A |
| Alias symbols | BI; EA2; FHM; MHP; APCA; HPCA; MHP1; SCA6; CAV2.1; CACNL1A4 |
| Gene name | calcium channel, voltage-dependent, P/Q type, alpha 1A subunit |
| Gene map locus | 19p13; chr19:13,206,442-13,633,025(-) |
| Ensembl Gene ID | ENSG00000141837 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016] |
| Repeat unit | CAG |
| Normal repeat copies | 4-18 |
| Pathogenic repeat copies | ≥20 |
| Gene | CACNA1A |
| Repeat location | CDS |
| Chromosome locus | chr19:13207857-13207897 (-) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | Kordasiewicz et al. (2006) found that a 75-kD C-terminal fragment of CACNA1A, which is the location of the polyglutamine tract expanded in SCA6, is cleaved from the full-length protein and translocated to the nucleus, where it is toxic to cells when in the expanded state. The polyglutamine-mediated cell toxicity was dependent on nuclear localization, suggesting that specific processing and localization of the mutant protein is involved in the pathogenesis of SCA6.
Li et al. (2009) confirmed that C-terminal fragments of CACNA1A localized predominantly to the nucleus of HEK293 cells where they existed as speckle-like structures resembling promyelocytic leukemia nuclear bodies (PMLNBs). HEK293 cells expressing an expanded (24 CAG repeats) C-terminal end of CACNA1A showed decreased viability when exposed to toxic cadmium compared to cells with nonexpanded (13 CAG) repeats. However, there were no differences in viability under normal culture conditions. Cadmium treatment also disrupted the PMLNBs and enhanced aggregation of C-terminal CACNA1A fragments, particularly in CAG-expanded cells. Immunocytochemical studies showed that cadmium-induced death was caspase-3 (CASP3; 600636)-dependent, indicating apoptosis. Gene expression studies showed downregulation of the HSF1 (140580)-HSPA1A (140550) axis as an event in 24-CAG repeat cells that appeared to be critical for cellular toxicity. The findings were consistent with SCA6 pathogenesis being related to polyglutamine diseases. [By OMIM] |
| Pathway annotation | Reactome, KEGG |
| PMID | 12707077 |
| Authors | Alonso I, Barros J, Tuna A, Coelho J, Sequeiros J, Silveira I, Coutinho P |
| Title | Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family |
| Journal | Arch Neurol. 60(4):610-4 |
| Year | 2003 |
| PMID | 18285829 |
| Authors | Craig K, Takiyama Y, Soong BW, Jardim LB, Saraiva-Pereira ML, Lythgow K, Morino H, Maruyama H, Kawakami H, Chinnery PF |
| Title | Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: founder effect or predisposing chromosome? |
| Journal | Eur J Hum Genet. 16(7):841-7 |
| Year | 2008 |